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Come considerare la positività dei marker di necrosi dopo

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1 Come considerare la positività dei marker di necrosi dopo
procedure interventistiche coronariche Stefano Savonitto, Claudio Cavallini Dipartimento di Cardiologia e Cardiochirurgia “Angelo De Gasperis” Ospedale Niguarda Ca’ Granda, Milano Divisione di Cardiologia, Pr. Osp. Ca’ Foncello, Treviso

2 Elevazione degli indicatori di danno miocardico dopo rivascolarizzazione percutanea
CK-MB 10-25% Troponina T o I %

3 ECS/ACC Consensus document for redefinition of Myocardial infarction
Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB)of biochemical markers of myocardial necrosis (above 99th percentile) with at least one of the following. (a) ischemic symptoms (b) development of Q-wave at ecg (c) ECG changes indicative of ischemia (d) coronary artery intervention      Eur Heart J.2000;

4 ACC/AHA percutaneous coronary guidelines
…The writing committee recommends that a CK-MB determination be performed on all patients who have signes or sympthoms suggestive of MI following the procedure or in patients in whom there is angiographic evidence of abrupt vessel closure, important side branch occlusion, or persistent slow flow. (in these circumstances)…., a CK-MB > 3 times the upper limit of normal would constitute a clinically significant MI J Am Coll Cardiol 2001; 37:1-66

5 Minor Myocardial Damage and prognosis:
Are spontaneous and PCI-related events differents? 6-months mortality CK-MB/ULN SPONTANEOUS POST- PCI R.R. R.R. p 0-1 >1-3 >3-5 >5-10 >10 4.1 1.3 0.33 0.54 0.71 0.23 Spontaneous MI - GUSTO IV ACS, PURSUIT Post PCI MI- EPIC, EPILOG, Capture, IMPACT II, PURSUIT Akkerhuis, JACC 2001;37:355a

6 Problemi nella interpretazione degli studi ck-release/prognosi
studi retrospettivi o analisi post-hoc selezione dei pazienti (trial clinici) inadeguata durata follow-up assenza di analisi multivariata insufficiente dimensione del campione

7 CK-RELEASE dopo PCI Substrato fisiopatologico
Correlati clinici, angiografici e procedurali Impatto prognostico Esiste un rapporto di causa/effetto?

8 Post-PCI CK-MB elevation represents myonecrosis
14 patients with no previous MI and TIMI 3 flow post procedure. 9 of these with CK-MB release (median 2.3X ULN) Anatomic correlate of myonecrosis seen with contrast MRI (median 2.0 grams of myocardium) Ricciardi Circulation 2001; 103:

9 Correlation of post-PCI CKMB elevation and
LV mass necrosis at contrast-enhanced MRI 15 10 5 Hyper- enhancement mass of LV (g) R=0.61 P=0.02 CKMB (ng/ml) Ricciardi Circulation 2001; 103:

10 CK-RELEASE dopo PCI Substrato fisiopatologico
Correlati clinici, angiografici e procedurali Impatto prognostico Esiste un rapporto di causa/effetto?

11 Condizioni cliniche più frequentemente associate a rilascio enzimatico
Età avanzata Pregresso infarto miocardico Pregresso intervento di bypass aorto-coronarico Ipercolesterolemia Insuccesso procedurale Insufficienza renale cronica Aterosclerosi sistemica

12 Clinical Characteristics associated with Post-Procedural
CK-MB elevation (CK-MB <16U) 1675 Patients, Mount Sinay Hospital, NY, NY Kini A, JACC 1999;34:663-71 Charact (%) Elevated CK-MB (n=313) Normal CK-MB (n=1362) P value Female CCS class III-IV Renal failure Systemic Atherosclerosis Abciximab Use Betablocker therapy 37 52 7 16 51 27 30 33 3 10 36 41 0.02 0.001 <0.001 Age, hypertension,hypercholesterolemia, smoking, diabetes, prior MI, prior revascularization, LVEF, CHF, MVD, IABP were found not related to CK-MB elevation

13 Risk of troponin elevation after PCI
a prospective substudy of SYMPHONY TnI >1.5 ng/ml (Dimension, Dade Behring, Detection limit 0.05 ng/ml) Positive TnI (n=230) Negative TnI (n=251) P value Age, y Female sex (%) Weight (kg) Current smoking (%) Diabetes (%) Family history of CAD (%) hypercholesterolemia (%) hypertension (%) 56 (48, 67) 21 86 (76, 99) 38 15 67 55 47 59 (50, 66) 28 83 (74, 94) 38 20 55 54 56 0.09 0.1 0.02 0.9 0.01 0.8 0.05 Cantor WJ, submitted

14 Risk of troponin elevation after PCI
a prospective substudy of SYMPHONY TnI >1.5 ng/ml (Dimension, Dade Behring, Detection limit 0.05 ng/ml) Medical history (%) Positive TnI (n=230) Negative TnI (n=251) P value Chronic Angina Bypass Surgery Previous MI Previous PCI Stroke Heart Failure Chronic Renal Insufficiency 43 16 18 2 5 0.4 52 15 23 18 1 3 0.05 0.9 0.2 0.4 0.3 0.5 Cantor WJ, submitted

15 Risk of troponin elevation after PCI
a prospective substudy of SYMPHONY TnI >1.5 ng/ml (Dimension, Dade Behring, Detection limit 0.05 ng/ml) Indication (%) Positive TnI (n=230) Negative TnI (n=251) P value Elective Recurr/Refract Ischemia Abrupt Closure Hemodynamic Instability (re)Infarction Days from qualyfying events 74 14 1.7 11 3 (2, 5) 77 20 0.4 2 11 (5, 32) 0.5 0.05 0.1 0.3 0.001 <0.001 Cantor WJ, submitted

16 Plaque Characteristics associated with Post-Procedural
CK-MB elevation (CK-MB <16U) 1675 Patients, Mount Sinai Hospital, NY, NY 30 25 20 15 10 5 P<0.001 % A B1 B2 C N=207 N=223 N=880 N=365 Kini A, JACC 1999;34:663-71

17 Angiographic Characteristics associated with Post-Procedural
CK-MB elevation (CK-MB <16U) 1675 Patients, Mount Sinai Hospital, NY, NY 30 25 20 15 10 5 P<0.001 % P<0.001 Entire Group Diffuse CAD Focal CAD Single vessel Intervention Multivessel Intervention Kini A, JACC 1999;34:663-71

18 Risk of troponin elevation after PCI
a prospective substudy of SYMPHONY TnI >1.5 ng/ml (Dimension, Dade Behring, Detection limit 0.05 ng/ml) Procedural Charact (%) Positive TnI (n=230) Negative TnI (n=251) P value Multivessel Intervention Target Vessel (native) Saphenous Vein Graft PTCA Stent Atherectomy or Laser Abciximab Use Angiographic Success 10 7 92 88 5 26 91 16 3.6 90 77 4 17 86 0.07 N.S. 0.1 0.5 0.002 0.7 0.02 No difference Cantor WJ, submitted

19 Device Characteristics associated with Post-Procedural
CK-MB elevation (CK-MB <16U) 1675 Patients, Mount Sinay Hospital, NY, NY Kini A, JACC 1999;34:663-71 30 25 20 15 10 5 % PTCA* PRCA** Stent PRCA+ stent Other devices *PTCA vs non-balloon devices **PRCA vs Stent N=174 N=420 N=477 N=534 N=70

20 Postprocedural cTnT elevation and total balloon inflation time
Johansen O, Eur Heart J 1998;19:112-7 N= 75 patients 12 9 6 3 1 Prevalence (%) 50 40 30 20 10 Risk Ratio <180 >307 Total inflation time (sec)

21 Cause di rilascio enzimatico
Insuccesso procedurale Embolia coronarica Occlusione acuta transitoria Ampia dissezione Occlusione di collaterali Fenomeno “no-reflow” Ostruzione microvascolare 50-60%

22 CK elevations in Coronary Artery Interventions
Angiographic correlates (Dobies R, AHA 1998) Prospective study: 774 pts Elevated CK (>160 mu/ml; MB>9.9 ng/ml) = 12% Angiographic evidence for CK elevation = 92% abrupt closure dissection 40% 6% thrombus 24% distal embolization 6% 17% 7% side branch occlusion decreased final TIMI flow

23 PCI, PLATELET AND MICROVASCULAR EMBOLIZATION
Debries and platelet-thrombin-WBC micro-emboli

24

25 TIMI Myocardial Perfusion Grade and Maximum CK-MB 24 Hours Post-stent
TIMI Grade 3 Flow: 100% CTFC: mean, median, 13 TIMI Grade 3 Flow: 100% CTFC: mean, median, 17.5, p=0.02 2.5 p = 0.01 2 1.5 Maximum CK-MB / Upper Limit of Normal The Corrected TIMI Frame Count was not related to CK-MB levels. 100% of patients achieved TIMI Grade 3 Flow post PCI and this was not related to the peak CK MB. While these measures of epicardial blood flow were not related to CK MB, the TIMI myocardial perfusion grade, a measure of tissue level perfusion was associated with the magnitude of CK-MB leak. Those patients with a closed myocardium or TIMI myocardial perfusion grades 0 or 1, had a significantly higher peak CK-MB with levels that were more than twice the upper limit of normal at their institution. 1 0.5 n = 24 n = 34 TMPG 3 TMPG 0/1/2 Gibson, AHJ, in press

26 Integrilin Improves Myocardial Perfusion After Stenting
% With Normal Blush DSA > 5.3 Gray Blush Circumference 20 P=0.085 69% P=0.079 15 48% Circumference (cm) % With Normal Blush 10 Recently we have found that integrilin administration improves coronary flow reserve. 5 N=16 N=27 N=32 N=24 Placebo Integrilin 180/2/180 Placebo Integrilin 180/2/180 CM Gibson 2000

27 CK-RELEASE dopo PCI Substrato fisiopatologico
Correlati clinici, angiografici e procedurali Impatto prognostico Esiste un rapporto di causa/effetto?

28 Clinical Relevance of CK elevation following PCI Northwestern University Experience 1984-1993
100 Sopravvissutil (%) p < 0.02 90 Controlli (n = 120) CK-MB >LSN (n = 253) 80 1 2 3 4 5 6 TEMPO (anni) Kong et al. JAMA. 1997

29 Elevated TnI and prognosis after PCI:
0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 30 60 90 120 150 180 210 240 270 300 Days From Intervention Freedom From Death or MI cTnI <1.5 ng/mL cTnI >1.5 ng/mL P =0.0028 _ Elevated TnI and prognosis after PCI: a prospective evaluation from the SYMPHONY STUDY Cantor WJ, submitted N=230 N=251

30 EPIC Periprocedural CPK Elevation and Mortality in 3 RCTs of GP IIb/IIIa Inhibitors Topol, Circulation 2000;101:570. EPILOG EPISTENT

31 Correlation Between Elevated Cardiac Markers and Long-term Mortality
% mortality at 42 days % mortality at 6 months2 8 20 7.5% 19.9% 6 6.0% 15 14.5% 4 12.6% 3.7% 3.4% 10 9.2% 2 Relationship between myocardial necrosis and morbidity Less myocardial injury during hospitalization in PURSUIT was shown to correlate to less long-term congestive heart failure, less cardiogenic shock, less atrioventricular block, less ventricular tachycardia, and less fibrillation. 1.7% 5 5.7% 1.0%  1-2  2-3  3-5  5-10  10 <0.4 <1.0 < <5.0 < 9.0 Cardiac Troponin 1 (ng/ML) CK-MB (x ULN) 1. Antman EM, et al. N Engl J Med. 1996; 335: Alexander JH et al. Circulation. 1999; Suppl 1:1-629.

32 Probability of 6-month Events By Max CK Ratio
across the spectrum of ACS: the GUSTO IIb study Probability of Death by Max CK Ratio Probability of Death or MI by Max CK Ratio 0,25 0,25 ST elevation Non ST elevation 0,2 0,2 0,15 0,15 0,1 0,1 0,05 0,05 NonST elevation ST elevation 2 4 6 8 10 12 14 16 18 20 5 10 15 20 Max CK Ratio Max CK Ratio Savonitto S, JACC 2002, in press

33 Cumulative survival (%)
Impact on survival of Electrocardiographic Q-waves and enzimatic myocardial infarction normal 1-3 x nl 1.0 2.0 Time (years) 40 20 60 80 100 Cumulative survival (%) 3-5 x nl 5-8 x nl > 8 x nl Q-wave Stone; Circulation 2001;104:642

34 CK-RELEASE dopo PCI Substrato fisiopatologico
Correlati clinici, angiografici e procedurali Impatto prognostico Esiste un rapporto di causa/effetto?

35 … o marker di un rischio coronarico più grave?
CK- Release dopo PCI Causa di una prognosi peggiore.. … o marker di un rischio coronarico più grave?

36 Microinfarti e prognosi

37 CK-RELEASE AND CAUSES OF DEATH
SUDDEN DEATH SUBSEQUENT REVASCULAR. MYOCARDIAL INFARCTION NO CARDIAC ORIGIN

38 CK-release e prognosi avversa: potenziali meccanismi
Microinfarti = microrientri = suscettibilità a eventi aritmici Microembolizzazione: compromissione di circoli collaterali preformati = suscettibilità all’ischemia acuta e alle aritmie Microembolizzazione = alterata funzione del microcircolo

39 Coronary Microvascular Dysfunction in DCM Prognosis
PET MBF dip ≤ 1.36 ml/min/g Neglia et al, Eur Heart J; 2000 (abs)

40 Epidemiology and prognostic impact of biochemical marker elevations
after percutaneous coronary interventions A multicenter survey sponsored by the Italian Working Group on Atherosclerosis, Thrombosis and Vascular Biology and the Italian Society of Invasive Cardiology (GISE) Chairmen: Claudio Cavallini, MD, Ospedale S. Maria dei Battuti, Treviso Stefano Savonitto, MD, Ospedale Niguarda Ca’ Granda, Milan Roberto Violini, MD, Ospedale San Camillo, Rome

41 To evaluate prospectically the prognostic
Primary objective To evaluate prospectically the prognostic impact of CK-MB elevations >2x ULN after PCI on total mortality at 24 months Secondary objectives To assess the incidence and risk determinants of enzyme and marker elevations after PCI To assess the predictive value of each marker of necrosis and inflammation, and their combination on the aggregate of death,MI and clinical restenosis To assess the risk of early (subacute stent thrombosis) and late (clinical restenosis) events and their association with biochemical variables and predefined genetical polimorphisms

42 All of the patients undergoing PCIs during the study period
Inclusion criteria All of the patients undergoing PCIs during the study period Exclusion criteria Only patients not willing to participate in the study The study monitors will compare the study enrollment log with the Cath lab PCI log: centers enrolling <90% of their patients will be axcluded from the study PCI procedures and pharmacological interventions are to be carried out according to local routine

43 Baseline: immediately prior to PCI
Blood sampling 6 to 10 hours after the procedure 16 to 24 hours after the procedure Both plasmas and sera will be stored from each sampling, together with the cells for genetic determinations. All biological material will be sent to the central laboratory for biochemical and genetic determinations.

44 Mass CK-MB TnI C-reactive protein Serum Creatinine (substudy) Biochemical markers PlA1/PlA2 polimorphism for the platelet GPIIIa receptor Polimorphism for the platelet GPIa receptor Polimorphism I/D for the ACE gene Genetic determinations

45 ARRUOLAMENTO NEI VARI CENTRI
TREVISO GENOVA MILANO Niguarda MERCOGLIANO BRESCIA (O.C.) CUNEO COTIGNOLA PAVIA UDINE NOVARA ROMA PARMA LEGNANO BOLZANO BRESCIA (P.A.) MIRANO

46 Enrolment in the Italian PCI -BM (Biochemical Marker) study
Month (yr 2000) 4039 patients Enrolment in the Italian PCI -BM (Biochemical Marker) study 16 participating centers Ist patient February 1st Last patient October 31

47 Conclusioni Rilascio enzimatico dopo PCI o CABG: frequente
Significato prognostico ?: sfavorevole (++ in > 5-10 volte LSN) Raccomandazione : prevenire Come trattare? : prevenzione secondaria The end


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